PROJECT SUMMARY (OVERALL) This is a renewal application to continue the Brittle Bone Disorders Consortium of the Rare Diseases Clinical Research Network (BBDC RDCRN) for years 6-10. The BBDC is focused on rare bone diseases that are caused by defects in osteoblast differentiation and/or function which leads to qualitative and/or quantitative defects of bone, altered biomaterial properties such as mineralization, and/or downstream cellular changes in osteocytes and osteoclasts. These are represented by the different types of Osteogenesis Imperfecta (OI). While OI is often used interchangeably with BBD, the phenotypic spectrum is rapidly expanding. Moreover, there is a significant unmet need to understand the natural history of these phenotypes stratified by their molecular genetic etiologies. How these different mutations ultimately lead to brittle bone remains unknown and what are appropriate interventions and biomarkers of various disease morbidities are open questions. In years 1-5 of the BBDC, we met or exceeded accrual targets in 6 out of 7 protocols. We have published or have under review 12 manuscripts describing our cross sectional data. Importantly, our findings in the previous longitudinal study, pregnancy study, craniofacial study, pilot collagen crosslink biomarker study, and the PROMIS pilot study have empowered the design and inclusion of new elements in the current longitudinal study (Project 1), orthodontic clinical trial to treat malocclusion in OI (Project 2), and longitudinal biomarker study of growth (Project 3). This BBDC will be composed of 12 clinical sites covering the U.S. and Canada. The Specific Aims of the BBDC are: i) To perform collaborative clinical research in brittle bone disorders including the three clinical projects listed above; ii) To train and attract a cohort of investigators in clinical bone research who will be recruited from undergraduate, post-baccalaureate, graduate, medical student, resident/fellow, and junior faculty ranks; and iii) to collaborate with the Osteogenesis Imperfecta Foundation (OIF) to expand a tool box of training materials that can be used to broadly educate patients, families, and healthcare provider across a broad spectrum of expertise.